Ever since antibiotics were first used it was appreciated that bacteria could display intrinsic resistance to these drugs or could develop resistance to these drugs. Resistance of a bacterium to an antibiotic can be viewed as a substantially greater tolerance, or reduced susceptibility, to the antibiotic compared to a sensitive bacterium or a typical or a wild type version of the bacterium. In some cases a bacterium can be completely unaffected by exposure to an antibiotic. In this instance the bacterium can be considered fully resistant to that antibiotic.
Multidrug resistance (MDR) in bacteria describes the situation where a bacterium is resistant to at least three classes of drugs, specifically in the context of bacteria, at least three classes of anti-microbial (or more specifically anti-bacterial) agents, and particularly in the context of the present invention, at least three classes of antibiotics. Antibiotics in one class are functionally unrelated, structurally unrelated, or both, to antibiotics in a different class. MDR in bacteria is thus often termed multiple anti-bacterial drug resistance or multiple antibiotic resistance. The terms are used interchangeably in the art and herein. Bacteria displaying multidrug resistance phenotypes (or multiple antibacterial/antibiotic drug resistance phenotypes) are referred to as MDR bacteria (or sometimes MAR bacteria). Again, these terms are used interchangeably in the art and herein.
Antibiotic resistance mechanisms are numerous. For instance, resistance may arise from impermeability mechanisms which physically prevent the antibiotic reaching its site of action in or on the bacterium; efflux mechanisms which prevent effective amounts of the antibiotic reaching its site of action in or on the bacterium by rapidly removing the antibiotic from the bacterium; metabolic mechanisms which breakdown the antibiotic or convert the antibiotic into a harmless (or less harmful) compound, or a compound more easily excreted; bypass mechanisms in which the bacterium uses alternative pathways to those inhibited by the antibiotic; or through the bacterium having a form of the antibiotic target (e.g. enzyme) that is less sensitive to the antibiotic or not having the target at all.
Resistance to a particular antibiotic or class of antibiotic may be intrinsic to the bacterium, but it can also be developed or acquired. Generally intrinsic resistance may be seen to a particular type or class of antibiotic, but the number of different antibiotic classes to which resistance is seen is usually restricted. Resistance to numerous classes of antibiotics (including to multiple classes of antibiotics, which is defined herein as at least three classes of antibiotics) may be an acquired (or developed) phenomenon, but this is not exclusively the case. Thus, in the case of MDR bacteria, the bacteria may acquire or develop resistance to particular antibiotic classes (e.g, to one or more or two or more classes, for example additional classes, or to 3 or more classes), or in certain cases the bacteria may be intrinsically resistant to multiple classes. The resistant phenotype of MDR bacteria can differ from typical or wild type bacteria, but certain bacteria can be considered MDR on account of their intrinsic resistance profile, e.g. Burkholderia species including Burkholderia cepacia, Burkholderia mallei, and Burkholderia pseudomallei. 
Development (or acquisition) of resistance can be through mutation. For instance, this may involve changes in the structure of the target of the antibiotic that reduces the sensitivity of the target to the antibiotic. It can also be a mutation in a pathway involved in the regulation of the cellular machinery involved in the metabolism or efflux of the antibiotic. It can also be a mutation in the constituents of the outer layers (e.g. the membranes/walls) of the bacterium that effects the permeability of the antibiotic into the bacterium. In some instances multiple mutations must accumulate in order for a bacterium to become resistant to a particular antibiotic or class thereof.
Development of resistance can also be through the transfer of a resistance mechanism from another organism, e.g. another bacterium (this is sometimes referred to as acquired resistance, but as used herein the term “acquired resistance” includes any means or mechanism by which the resistance arises, including by transfer or by mutation). This is usually, although not exclusively, though the transfer from organism to organism of mobile nucleic acids encoding the resistance mechanism (e.g. β-lactamase).
As a consequence of the inherent selective pressure antibiotics exert on a bacterial population, the use of antibiotics selects for resistant members of that population. The sequential use of different antibiotics in a treatment regime can therefore give rise to MDR bacteria.
Many MDR species and strains of bacteria exist today. Bacterial genera from which MDR species and strains pose significant problems for human and animal health include, but are not limited to Pseudomonas, Acinetobacter, Burkholderia, Klebsiella, Providencia, and Staphylococcus 
Pseudomonas is a genus of strictly aerobic, gram-negative bacteria of relatively low virulence. Nevertheless, Pseudomonas species can act as opportunistic pathogens and infections have been reported with Pseudomonas aeruginosa, Pseudomonas oryzihabitans, Pseudomonas luteola, Pseudomonas anguilliseptica and Pseudomonas plecoglossicida. 
P. plecoglossicida and P. anguilliseptica are fish pathogens. P. oryzihabitans can be a human pathogen causing peritonitis, endophthalmitis, septicemia and bacteriaemia. Similar infections can be caused by P. luteola. The majority of Pseudomonas infections in humans are, however, caused by P. aeruginosa. 
P. aeruginosa is a widespread and extremely versatile bacteria that can be considered a part of the natural flora of a healthy subject and is capable of colonising most man-made environments. This ubiquity and versatility has seen colonisation of healthcare environments by P. aeruginosa. Problematically, the same versatility enables P. aeruginosa to act as an opportunistic human pathogen in impaired subjects, most commonly immunocompromised patients (e.g. those with, cystic fibrosis or AIDS) and patients with a compromised barrier to infections (e.g. those with chronic wounds and burns and those with in-dwelling medical devices such as intravenous lines, urinary catheters, dialysis catheters, endotracheal tubes).
P. aeruginosa infection can affect many different parts of the body, but infections typically target the respiratory tract, the GI tract, the urinary tract and surface wounds and burns and in-dwelling medical devices. This problem is compounded by the presence of intrinsic resistance to many of the β lactam antibiotics. Acquired resistance of certain strains to further antibiotics is also being reported. The ability of certain strains of P. aeruginosa to form biofilms adds further to these problems because biofilm-dwelling bacteria are often more resistant to anti-microbials than their non-biofilm counterparts. As such, there is an urgent need for safe and effective treatments for Pseudomonas infections and contamination and, in particular, treatments that overcome antibiotic resistance, particularly β-lactam resistance, in Pseudomonas species.
Burkholderia is a genus of gram-negative, motile, obligate aerobic, non-fermenting rod-shaped bacteria. Burkholderia species are widely distributed in nature and include animal and plant pathogens. Burkholderia cepacia is emerging as a human pathogen of note. B. cepacia has been reported to have caused necrotizing pneumonia, ventilator-associated pneumonia, bacteraemia, and infections of the skin, soft tissue, bloodstream, respiratory tract, and urinary tract in cystic fibrosis patients and hospitalised patients. Burkholderia cepacia is a part of a group of at least nine different species forming the Burkholderia cepacia complex (BCC), including B. multivorans, B. cenocepacia, B. vietnamiensis, B. stabilis, B. ambifaria, B. dolosa, B. anthina, and B. pyrrocinia 
Burkholderia pseudomallei, is the causative agent of melioidosis, a potentially fatal community-acquired infectious disease endemic to southeast Asia, Taiwan and northern Australia. Cases have also been described in China, India, Central and South America, the Middle East, and several African countries. Incidences of the disease amongst servicemen engaged in conflicts in these areas have been reported and spread of the diseases back to the country of origin of these servicemen has been noted and is a consequence of the fact that relapses are common and the disease can remain latent for long periods before clinical manifestation.
Burkholderia mallei, is the causative agent of glanders, an infectious disease that primarily affecting horses, mules and donkeys, but it has been reported in other animals, e.g. dogs, cats and goats, and in particular, transmission to humans can occur. Transmission from the animal to human typically occurs by direct contact through skin abrasions, nasal and oral mucosal surfaces, or by inhalation.
Problematically, pathogenic Burkholderia species often display intrinsic resistance to multiple antibiotics and antibiotic classes (e.g. one of more of the aminoglycosides, β-lactams and macrolides) and persistence in betadine (a topical antiseptic used commonly in hospitals) has been noted. Acquired resistance of certain strains to further antibiotics is also being reported. As such, there is an urgent need for safe and effective treatments for Burkholderia infections and contamination and, in particular, treatments that overcome antibiotic resistance, particularly, β-lactam and macrolide resistance, in Burkholderia species.
Providencia is a genus of gram-negative bacilli that are responsible for a wide range of human infections. Providencia infections are usually nosocomial and are found predominantly in the urinary tract, often as a consequence of catheterisation. Providencia infections are also associated with gastroenteritis and bacteraemia and surface infections of chronic wounds and burns. They represent an emerging problem because of the increasing prevalence of strains with β-lactam antibiotic resistance due to the spread amongst Providencia populations of extended-spectrum beta-lactamase (ESBL).
Providencia species include Providencia stuartii, Providencia sneebia, Providencia rettgeri, Providencia rustigianii, Providencia heimbachae, Providencia burhodogranariea and Providencia alcalifaciens. Providencia species have been found in soil, water and sewage and in multiple animal reservoirs. Examples of Providencia infections in animals include neonatal diarrhoea in cattle due to P. stuartii infection and enteritis caused by P alcalifaciens infection in dogs. P. rettgeri has been isolated in crocodiles with meningitis/septicaemia and in chickens with enteritis. P. heimbachae has been isolated in penguin faeces and aborted bovine foetuses.
In humans, Providencia species have been isolated from urine, stool, and blood, as well as from sputum, skin, and wound cultures. P. stuartii is frequently isolated in patients with indwelling urinary catheters and is known to persist in the urinary tract after bladder access is attained. P. stuartii can give rise to septicaemia, and commonly this is secondary to the infection of the urinary tract. P. stuartii has also been reported as the etiology of infective endocarditis. P. rettgeri has been reported to be a cause of ocular infections, including keratitis, conjunctivitis, and endophthalmitis. P. alcalifaciens, P. rettgeri, and P. stuartii have also been implicated in gastroenteritis.
Providencia infections with antimicrobial resistance patterns are increasing and ESBL-positive P. stuartii is an increasing problem in hospitalized patients. As such, there is an urgent need for safe and effective treatments for Providencia infections and contamination and, in particular, treatments that overcome antibiotic resistance, particularly β-lactam resistance, in Providencia species.
Acinetobacter is a genus of bacteria that are strictly aerobic non-fermentative gram-negative bacilli. Acinetobacter species are widely distributed in nature and can survive for long periods of time on wet or dry surfaces. Acinetobacter species are considered to be non-pathogenic to healthy subjects, but it is becoming increasingly apparent that Acinetobacter species persist in hospital environments for a long period of time and can be responsible for nosocomial infections in compromised patients. Acinetobacter baumannii is a frequent cause of nosocomial pneumonia, especially of late-onset ventilator associated pneumonia and it can cause various other infections including skin and wound infections, bacteraemia, and meningitis. Acinetobacter lwoffii has also been associated with meningitis. Other species including Acinetobacter haemolyticus, Acinetobacter johnsonii, Acinetobacter junii, Acinetobacter radioresistens, Acinetobacter tandoii, Acinetobacter tjernbergiae, Acinetobacter towneri, or Acinetobacter ursingii have also been linked to infection. Of particular note is the prevalence of Acinetobacter baumannii infections in US serviceman stationed in the Middle East, e.g. Iraq. Of concern is the fact that many Acinetobacter strains appear to be multidrug resistant, thus making the combat of Acinetobacter infections and contamination difficult. As such, there is an urgent need for safe and effective treatments for Acinetobacter infections and contamination.
Klebsiella is a genus of non-motile, gram-negative, rod shaped bacteria Klebsiella species are ubiquitous in nature. In humans, they may colonize the skin, pharynx, and gastrointestinal tract and may be regarded as normal flora in many parts of the colon, the intestinal tract and in the biliary tract.
Klebsiella species include, Klebsiella granulomatis, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella singaporensis, and Klebsiella variicola, although K pneumoniae and K oxytoca are the members of this genus responsible for most human infections. Such infections include pneumonia, bacteraemia, thrombophlebitis, urinary tract infection, cholecystitis, diarrhoea, upper respiratory tract infection, wound infection, osteomyelitis, and meningitis. Rhinoscleroma and ozena are two other infections caused by Klebsiella species. Rhinoscleroma is a chronic inflammatory process involving the nasopharynx, whereas ozena is a chronic atrophic rhinitis characterized by necrosis of nasal mucosa and mucopurulent nasal discharge.
Klebsiellae often contribute to nosocomial infections. Common sites include the urinary tract, lower respiratory tract, biliary tract, and wounds. The presence of invasive devices, in particular respiratory support equipment and urinary catheters, increase the likelihood of nosocomial infection with Klebsiella species. Sepsis and septic shock may follow entry of organisms into the blood from these sources.
K. pneumoniae is an important cause of community-acquired pneumonia in elderly persons and subjects with impaired respiratory host defences. K. oxytoca has been implicated in neonatal bacteraemia, especially among premature infants and in neonatal intensive care units. Increasingly, the organism is being isolated from patients with neonatal septicaemia.
Problematically, resistance of Klebsiella species to antibiotics is increasing. As such, there is an urgent need for safe and effective treatments for Klebsiella infections and contamination and, in particular, treatments that overcome antibiotic resistance in Klebsiella species.
Antibiotics are a key tool in the clinical management of bacterial infections, e.g. those involving the genera mentioned above. Unfortunately, the number of antibiotics available to physicians is finite and has remained largely unchanged for many years. Resistance of a bacterium to an antibiotic reduces the number of antibiotics available to treat the bacterium. Bacteria resistant to multiple antibiotics are therefore proportionately more difficult to treat. Continued use of antibiotics inevitably selects for MDR bacteria and so there is an urgent need for techniques by which MDR phenotypes can be overcome. The inventors have surprisingly found that alginate oligomers can achieve this. Alginates are linear polymers of (1-4) linked β-D-mannuronic acid (M) and/or its C-5 epimer α-L-guluronic acid (G). The primary structure of alginates can vary greatly. The M and G residues can be organised as homopolymeric blocks of contiguous M or G residues, as blocks of alternating M and G residues and single M or G residues can be found interspacing these block structures. An alginate molecule can comprise some or all of these structures and such structures might not be uniformly distributed throughout the polymer. In the extreme, there exists a homopolymer of guluronic acid (polyguluronate) or a homopolymer of mannuronic acid (polymannuronate).
Alginates have been isolated from marine brown algae (e.g. certain species of Durvillea, Lessonia and Laminaria) and bacteria such as Pseudomonas aeruginosa and Azotobacter vinelandii. Other pseudomonads (e.g. Pseudomonas fluorescens, Pseudomonas putida, and Pseudomonas mendocina) retain the genetic capacity to produce alginates but in the wild they do not produce detectable levels of alginate. By mutation these non-producing pseudomonads can be induced to produce stably large quantities of alginate.
Alginate is synthesised as polymannuronate and G residues are formed by the action of epimerases (specifically C-5 epimerases) on the M residues in the polymer. In the case of alginates extracted from algae, the G residues are predominantly organised as G blocks because the enzymes involved in alginate biosynthesis in algae preferentially introduce the G neighbouring another G, thus converting stretches of M residues into G-blocks. Elucidation of these biosynthetic systems has allowed the production of alginates with specific primary structures (WO 94/09124, Gimmestad, M et al, Journal of Bacteriology, 2003, Vol 185(12) 3515-3523 and WO 2004/011628).
Alginates are typically isolated from natural sources as large high molecular weight polymers (e.g. an average molecular weight in the range 300,000 to 500,000 Daltons). It is known, however, that such large alginate polymers may be degraded, or broken down, e.g. by chemical or enzymatic hydrolysis to produce alginate structures of lower molecular weight. Alginates that are used industrially typically have an average molecular weight in the range of 100,000 to 300,000 Daltons (such alginates are still considered to be large polymers) although alginates of an average molecular weight of approximately 35,000 Daltons have been used in pharmaceuticals.